U.S. patent number 3,883,651 [Application Number 05/499,460] was granted by the patent office on 1975-05-13 for pharmaceutical compositions containing a 2-(aminoalkylamino)-4-amino-thieno[3,2-d]pyrimidine and method of use.
This patent grant is currently assigned to Boehringer Ingelheim G.m.b.H.. Invention is credited to Berthold Narr, Wolfgang Schroter, Eberhard Woitun.
United States Patent |
3,883,651 |
Woitun , et al. |
May 13, 1975 |
Pharmaceutical compositions containing a
2-(aminoalkylamino)-4-amino-thieno[3,2-d]pyrimidine and method of
use
Abstract
Pharmaceutical dosage unit compositions containing as an active
ingredient a compound of the formula ##SPC1## Wherein R and R.sub.1
may be the same or different and are selected from the group
consisting of hydrogen and straight and branched alkyl of 1 to 6
carbon atoms and taken together with the nitrogen atom to which
they are attached form a saturated 5 to 7 member heterocyclic ring
which can optionally contain an oxygen or nitrogen heteroatom and
may be substituted with alkyl of 1 to 6 carbon atoms or hydroxyl,
R.sub.2 is selected from the group consisting of hydrogen and
straight and branched alkyl of 1 to 6 carbon atoms, R.sub.3 is
selected from the group consisting of methyl in in the 6- or
7-position and hydrogen and A is a straight or branched alkylene of
2 to 10 carbon atoms Or a non-toxic, pharmaceutically acceptable
acid addition salt thereof; and methods of using the same for
inhibiting platelet aggregation in warm-blooded animals.
Inventors: |
Woitun; Eberhard (Biberach an
der Riss, DT), Narr; Berthold (Biberach an der Riss,
DT), Schroter; Wolfgang (Biberach an der Riss,
DT) |
Assignee: |
Boehringer Ingelheim G.m.b.H.
(Ingelheim am Rhein, DT)
|
Family
ID: |
27510063 |
Appl.
No.: |
05/499,460 |
Filed: |
August 22, 1974 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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60933 |
Aug 4, 1970 |
3838121 |
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Foreign Application Priority Data
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Aug 8, 1969 [DT] |
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1940572 |
Jul 2, 1970 [DT] |
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2032686 |
Jul 2, 1970 [DT] |
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2032687 |
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Current U.S.
Class: |
514/234.2;
514/260.1 |
Current CPC
Class: |
C07D
495/04 (20130101) |
Current International
Class: |
C07D
495/04 (20060101); C07D 495/00 (20060101); A61u
027/00 () |
Field of
Search: |
;424/248,251 |
Other References
Thomae, Chem. Abstracts, Vol. 67, p. 100149g (1967)..
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Primary Examiner: Friedman; Stanley J.
Attorney, Agent or Firm: Hammond & Littell
Parent Case Text
This is a division of copending application Ser. No. 60,933 filed
Aug. 4, 1970, now U.S. Pat. No. 3,838,121.
Claims
We claim:
1. A pharmaceutical dosage unit composition consisting essentially
of an inert pharmaceutical carrier and an effective platelet
inhibiting amount of a compound of the formula ##SPC17##
wherein
R.sub.1 is hydrogen or methyl,
R.sub.2 is hydrogen, methyl or ethyl,
R.sub.3 is hydrogen, 6-methyl or 7-methyl, and
A is straight or branched alkyl of 2 to 6 carbon atoms, or a
non-toxic, pharmaceutically acceptable acid addition salt
thereof.
2. A composition of claim 1, wherein said compound is selected from
the group consisting of 2-[(5-aminopentyl)ethylamino]
-4-morpholino-thieno[3,2-d]pyrimidine and its non-toxic,
pharmaceutically acceptable acid addition salts.
3. A composition of claim 1, wherein said compound is selected from
the group consisting of
2-[(5-aminopentyl)methylamino]-4-morpholino-thieno[3,2-d]pyrimidine
and its non-toxic, pharmaceutically acceptable acid addition
salts.
4. A composition of claim 1, wherein said compound is selected from
the group consisting of 2-[(3-aminopropyl)-ethylamino]
-4-morpholino-thieno[3,2-d]pyrimidine and its non-toxic,
pharmaceutically acceptable acid addition salts.
5. A composition of claim 1, wherein said compound is selected from
the group consisting of
2-[(2-aminoethyl)ethylamino]-4-morpholino-thieno[3,2-d]pyrimidine
and its non-toxic, pharmaceutically acceptable acid addition
salts.
6. A composition of claim 1, wherein said compound is selected from
the group consisting of
2-(2-aminoethylamino)-4-morpholino-thieno[3,2-d]pyrimidine and its
nontoxic, pharmaceutically acceptable acid addition salts.
7. A composition of claim 1, wherein said compound is selected from
the group consisting of
2-(3-aminopropylamino)-4-morpholino-thieno[3,2-d]pyrimidine and its
nontoxic, pharmaceutically acceptable acid addition salts.
8. A composition of claim 1, wherein said compound is selected from
the group consisting of 2-(4-aminobutylamino)-4-morpholino-thieno[
3,2-d]pyrimidine and its nontoxic, pharmaceutically acceptable acid
addition salts.
9. A composition of claim 1, wherein said compound is selected from
the group soncisting of
2-[(2-aminoethyl)methylamino]-4-morpholino-thieno[3,2-d]pyrimidine
and its non-toxic, pharmaceutically acceptable acid addition
salts.
10. A composition of claim 1, wherein said compound is selected
from the group consisting of
2-(2-aminopropylamino)-4-morpholino-thieno[3,2-d]pyrimidine and its
nontoxic, pharmaceutically acceptable acid addition salts.
11. The method of inhibiting platelet aggregation in a warm-blooded
animal in need of such treatment, which comprises administering to
said animal an effective platelet aggregation inhibiting amount of
a compound of the formula ##SPC18##
wherein
R.sub.1 is hydrogen or methyl,
R.sub.2 is hydrogen, methyl or ethyl,
R.sub.3 is hydrogen, 6-methyl or 7-methyl, and
A is straight or branched alkyl of 2 to 6 carbon atoms, or a
non-toxic, pharmaceutically acceptable acid addition salt thereof.
Description
This invention relates to novel pharmaceutical compositions
containing as an active ingredient a
2-(aminoalkylamino)-4-amino-thieno[3,2-d]pyrimidine or a non-toxic
acid addition salt thereof, as well as to methods of using the same
as platelet aggregation inhibitors.
More particularly, the present invention relates to novel
pharmaceutical dosage unit compositions consisting essentially of
an inert pharmaceutical carrier and an effective platelet
aggregation inhibiting amount of a compound of the formula
##SPC2##
Wherein
R and R.sub.1 may be the same or different and are selected from
the group consisting of hydrogen and straight and branched alkyl of
1 to 6 carbon atoms and taken together with the nitrogen atom to
which they are attached form a saturated 5 to 7 member heterocyclic
ring which can optionally contain an oxygen or nitrogen heteroatom
and may be substituted with alkyl of 1 to 6 carbon atoms or
hydroxyl,
R.sub.2 is selected from the group consisting of hydrogen and
straight and branched alkyl of 1 to 6 carbon atoms,
R.sub.3 is selected from the group consisting of methyl in the 6-
or 7-position and hydrogen and
A is a straight or branched alkylene of 2 to 10 carbon atoms
Or a non-toxic, pharmaceutically acceptable acid addition salt
thereof.
Among the preferred compounds of formula I are those where R and
R.sub.1, together with the nitrogen atom to which they are
attached, form a morpholino ring optionally substituted with a
methyl group.
The acid addition salts of the thieno [3,2-d]pyrimidines of formula
I may be derived from non-toxic, pharmaceutically acceptable
inorganic acids such as hydrochloric acid, sulfuric acid,
phosphoric acid, etc., and organic acids such as succinic acid,
tartaric acid, maleic acid, fumaric acid, etc.
The thieno[3,2-d]pyrimidines of formula I may be made by the
following methods.
Method A
By reaction of a compound of the formula ##SPC3##
Wherein R, R.sub.1 and R.sub.3 have the above meanings and Z is a
halogen atom, a substituted mercapto group or an alkylsulfonyl
group with a diamine of the formula ##SPC4##
wherein R.sub.2 and A are as defined above and X is a hydrogen atom
or a protecting group easily split off, for example, acetyl,
benzoyl or p-toluenesulfonyl group, and optionally splitting off
the protecting group X.
If the radical Z is a halogen atom, the presence of a hydrogen
halide binding agent is required.
The reaction is performed at temperatures between 20.degree. and
200.degree.C, preferably in the presence of an organic solvent. The
hydrogen halide binding agent may be an inorganic or tertiary
organic base. There may, however, also be used at least a molar
excess of the employed diamine of general formula III as acid
binding agent. A further excess of the diamine may serve as the
solvent. If X represents a protecting group, this is split off
subsequently, for example by means of hydrolysis.
Method B
By reaction of a compound of the formula ##SPC5##
wherein the radicals R.sub.2, R.sub.3, X and A have the above
meanings and Z' is a halogen atom, a free or substituted mercapto
group or an alkylsulfonyl group with an amine of the formula
##SPC6##
wherein R.sub.1 and R are as defined above, and optionally
splitting off a protecting group X. If Z' is a halogen atom, the
presence of a hydrogen halide binding agent is required for the
reaction.
The reaction is performed at temperatures between 20.degree. and
200.degree.C, preferably in the presence of an organic solvent. The
hydrogen halide binding agent may be an inorganic or tertiary
organic base. There may, however, also be used at least one molar
excess of the employed amine as acid binding agent. A further
excess of this amine may serve as the solvent. If X is a protecting
group, this is optionally subsequently split off, for example by
means of hydrolysis.
Method C
By reaction of a compound of the formula ##SPC7##
wherein the radicals R to R.sub.3 and A are defined as above and Z"
is a halogen atom, with ammonia or with a carboxylic acid amide or
a carboxylic acid imide or their metal salts and by subsequent
splitting off of the acid group from the originating carboxylic
acid derivative.
The reaction is performed at temperatures between 20.degree. and
200.degree.C, preferably in the presence of an organic solvent.
When reacting with ammonia, the reaction is preferably carried out
with an excess of ammonia in a closed vessel. The carboxylic acid
derivative formed when using a carboxylic acid amide or imide is
split with acids or bases. Bases especially suitable are hydrazine
and hydroxylamine.
Method D
By catalytic reduction of a nitrile of the formula ##SPC8##
wherein the radicals R.sub.1, R.sub.2, R.sub.3 and R are defined as
in the beginning and the radical A' has the meaning of the radical
A minus a methylene group, however.
The reduction is advantageously carried out with hydrogen activated
in the presence of Raney-nickel, palladium or platinum catalysts at
elevated temperatures and elevated pressure. In general,
temperatures between 30.degree. and 100.degree.C at a pressure
between 20 and 150 atmospheres are sufficient.
Method E
Compounds of the formula I in which R.sub.1 and R together with the
nitrogen atom form a morpholino ring optionally substituted by an
alkyl group, are produced by intramolecular cyclization of a
compound of the formula ##SPC9##
wherein the radicals X, R.sub.2, R.sub.3 and A are defined as above
and R.sub.4 and R.sub.5 are hydrogen atoms or one of R.sub.4 or
R.sub.5 is an alkyl of 1 to 6 carbon atoms and the other is a
hydrogen atom in the presence of an acid condensation agent, and
optionally splitting off a protecting group X.
The reaction is carried out in the presence of an acid condensation
agent and optionally in a solvent at temperatures between 0.degree.
and 175.degree.C. The condensation agent may be acids such as
sulfuric acid, phosphoric acid, perchloric acid, hydrochloric acid,
hydrobromic acid, toluene sulfonic acid or anhydrous metal salts
such as zinc chloride or a cation exchanger. The solvents may be
higher hydrocarbons such as tetraline or the acid used as
condensation agent such as sulfuric acid or phosphoric acid. The
reaction may, however, also be performed in the melt form.
Moreover, it may be of advantage to perform the cyclisation under
an inert atmosphere. The protecting group X is optionally split off
subsequently, for example by means of hydrolysis.
The preparation of the compounds of formula II used as starting
materials is described in German Offenlegungsschrift No. 1,470,356,
wherein a 3-amino-thiophene-2-carboxylic acid of the formula
##SPC10##
or a reactive derivative thereof is reacted with urea or thiourea
or cyanic or thiocyanic acid. The reactive derivatives of the
3-aminothiophene-2-carboxylic acid proved to be especially suitable
are the esters and amides thereof. This forms compounds of the
formula ##SPC11##
wherein R.sub.3 has the above meanings and B is a free hydroxy or
mercapto group. If urea or cyanic acid is reacted with a compound
of formula IX, there is formed a compound of formula X, wherein B
is a free hydroxy group. If thiourea or thiocyanic acid is used
there is obtained a compound of formula X, in which B is the free
mercapto group. These reactions are generally performed at elevated
temperatures, preferably at temperatures between 20.degree. and
200.degree.C and optionally in the presence of water, when cyanic
or thiocyanic acid is used, or in the presence of an inert,
high-boiling solvent such as toluene, xylene or
tetrahydronaphthalene.
The compounds of formula II, in which Z is a halogen atom, are
produced by converting compounds of formula X, in which B is a free
hydroxy group, by conventional methods, for example by heating with
a phosphorus halide, first into a compound of the general formula
##SPC12##
in which Hal is a halogen atom. These compounds are then reacted at
room temperature or at slightly elevated temperatures in a solvent,
for example in ethanol, with compounds of formula V. Thus, the
starting compounds of formula II, wherein the radicals R.sub.1, R
and R.sub.3 are defined as above and Z is a halogen atom, are
formed.
For the production of compounds of formula II, in which Z is an
alkylmercapto or alkylsulfonyl group, compounds of formula X, in
which B is a free mercapto group, are converted by conventional
methods, by treating with alkylation agents, for example
dialkylsulfates or alkylhalides, into the corresponding
2-alkylmercapto-4-hydroxy-thieno[3,2-d]pyrimidines. These compounds
are converted by known methods, for example, by heating with a
phosphorus halide, into compounds of the formula ##SPC13##
wherein Alkyl is any alkyl group and Hal is a halogen atom. These
compounds are subsequently reacted at room temperature or at
slightly elevated temperatures in a solvent, for example in
ethanol, with compounds of formula V. Thus the starting materials
of formula II, wherein the radicals R.sub.1, R and R.sub.3 are
defined as above and Z is an alkylmercapto group, are formed. The
thus obtained compounds of formula II may subsequently be
converted, if desired, by means of oxidation agents, for example
chlorine or potassium permanganate, into such compounds of formula
II in which Z is an alkylsulfonyl group.
Compounds of general formula III, wherein X is a protecting group,
such as for example, acetyl, benzoyl or p-toluenesulfonyl group,
are produced according to methods known from the literature (see
Houben-Weyl, vol. XI/1, page 26 ff).
The compounds of formula IV are produced, for example, by reaction
of a 3-amino-thiophene-2-carboxylic acid of formula IX or a
reactive derivative thereof with thiourea or thiocyanic acid. The
reactive derivatives of the 3-aminothiophene-2-carboxylic acid
which proved to be especially suitable are their esters and amides.
Thereby are formed 2-mercapto-4-oxy-thieno[3,2-d]pyrimidines in
which the free mercapto group is subsequently alkylated by means of
alkyl halides to obtain
2-alkylmercapto-4-oxy-thieno[3,2-d]pyrimidines which are reacted
with diamines of formula III, ##SPC14##
wherein R.sub.2, X and A are defined as above, to the corresponding
2-aminoalkylamino-4-oxi-thieno[3,2-d]pyrimidines, after optionally
splitting off the radical X. These pyrimidines are subsequently
halogenated by means of phosphoroxyhalides to the starting
materials of formula IV, in which Z' is a halogen atom, or they
are, for example, converted by means of diphosphorus-pentasulfide
into the corresponding starting compounds of formula IV having a
mercapto group in 4-position. The thus obtained starting compound
of formula IV may subsequently be alkylated, if desired, by means
of alkyl halides by conventional methods to form a compound of
formula IV, in which Z' is an alkylmercapto group. These compounds
can easily be oxidized to compounds of formula IV, in which Z' is
an alkylsulfonyl group. The oxidation is preferably carried out by
means of chlorine or potassium permanganate.
The starting materials of formula VI are obtained by reaction of
2-hydroxyalkylamino-4-amino-thieno[3,2-d]pyrimidines of the formula
##SPC15##
wherein the radicals R to R.sub.3 and A are defined as above with
halogenation agents such as thionyl chloride. The reaction may be
perfomed in an inert solvent. The compounds of formula XIII are
known from the German Offenlegungsschrift No. 1,470,356 or may be
produced by the methods described therein.
The starting materials of formula VII are obtained by reaction of
aminonitriles of the formula ##SPC16##
wherein R.sub.2 is defined as above and A' has the meaning of A
minus a methylene group, with compounds of formula II. The
aminonitriles of formula XIV are partially known from the
literature or may be produced by methods described in the
literature (Houben-Weyl, Vol. XI/1, page 272 ff).
The starting materials of formula VIII may be produced from a
2,4-dichloro-thieno[3,2-d]pyrimidine of formula XI by reaction with
a diethanolamine and subsequently with an amine of formula III. If
X represents a protecting group, this may subsequently be split off
hydrolytically.
The novel compositions of the invention for inhibiting aggregation
of platelets are comprised of a compound of formula I or its
non-toxic, pharmaceutically acceptable acid addition salts and a
major amount of a pharmaceutical carrier. The compositions may be
in the form of drinkable or injectable solution or suspensions,
tablets, coated tablets, drops, etc. The usual individual dose is 5
to 100 mgm, preferably 10 to 50 mgm, of the active ingredient and
the daily dose is 100 to 200 mgm per day of the active
ingredient.
The method of the invention for inhibiting aggregation of platelets
in warm-blooded animals comprises administering to warm-blooded
animals an amount of a compound of formula I or its non-toxic,
pharmaceutically acceptable acid addition salts sufficient to
inhibit aggregation of platelets. The said compounds may be
administered transcutaneously or orally. The usual daily dose is
100 to 200 mgm/kg.
In the following examples, Examples I to XIV show the preparation
of starting materials and Example 1 to 15 show the preparation of
final products.
EXAMPLE I
1.6 gm (0.01 mol) of methyl 3-aminothiophene-2-carboxylate and 3 gm
(0.05 mol) of urea were admixed and then heated for 2 hours at
200.degree.C to obtain a clear brown melt which solidified when
cooled. The said product was dissolved in warm 2N aqueous sodium
hydroxide and the solution was decolorized with charcoal and made
acidic with 2N hydrochloric acid. The mixture was vacuum filtered
to recover the crystalline precipitate which was recrystallized
from water to obtain 1.2 gm (72% yield) of
2,4-dioxythieno[3,2-d]pyrimidine melting at more than
300.degree.C.
______________________________________ Analysis: C.sub.6 H.sub.4
N.sub.2 O.sub.2 S; molecular weight = 168.18 Calculated: C -
42.84%; H - 2.40%; N - 16.66%; Found: C - 42.75%; H - 2.57%; N -
16.82%; ______________________________________
Using the same procedure, urea was reacted with methyl
3-amino-5-methyl-thiophene-2-carboxylate and methyl 3-amino-4
-methyl-thiophene-2-carboxylate to form
2,4-dioxy-6-methyl-thieno[3,2-d]pyrimidine melting above
320.degree.C, and 2,4-dioxy-7-methyl-thieno[3,2-d]pyrimidine
melting above 300.degree.C, respectively.
EXAMPLE II
A mixture of 8.4 gm (0.05 mol) of 2,4-dioxy-thieno
[3,2-d]pyrimidine and 100 cc of phosphorus oxychloride was refluxed
for 10 hours to obtain a clear solution and excess phosphorus
oxychloride was distilled off in vacuo. The residual oil was added
to an ice-water mixture and then the mixture was extracted with
chloroform. The chloroform extract was washed with water until the
wash waters were neutral, dried over sodium sulfate and distilled
to dryness. The residue was crystallized from ethanol to obtain 7.6
gm (74% yield) of 2,4-dichloro-thieno[3,2-d]pyrimidine melting at
141.degree. to 142.degree.C.
______________________________________ Analysis: C.sub.6 H.sub.2
Cl.sub.2 N.sub.2 S; molecular weight = 205.08 Calculated: C -
35.13%; H - 0.98%; Cl - 34.58%; Found: C - 35.25%; H - 1.02%; Cl -
34.68%; ______________________________________
Using the same procedure, phosphorus oxychloride was reacted with
2,4-dioxy-6-methyl-thieno[3,2-d]pyrimidine and
2,4-dioxy-7-methyl-thieno[3,2-d]pyrimidine to obtain
2,4-dichloro-6-methyl-thieno[3,2-d]pyrimidine melting at
150.degree.C and 2,4-dichloro-7-methyl-thieno[3,2-d]pyrimidine
melting at 186.degree.C respectively.
EXAMPLE III
5.1 gm of (0.025 mol) of 2,4-dichloro-thieno[3,2-d] pyrimidine was
added to 200 cc of absolute ethanol and 4.8 gm (0.055 mol) of
morpholine were added with stirring to the resulting suspension
while keeping the temperature at 20.degree.C with cooling. The
resulting clear solution was allowed to stand for a short while
during which a crystalline compound precipitated out and then the
reaction mixture was stirred for 2 hours. After vacuum filtration,
the crystalline precipitate was washed with water, then ethanol.
The product was recrystallized from methyl ethyl ketone to obtain
5.75 gm (90% yield) of
2-chloro-4-morpholino-thieno[3,2-d]pyrimidine melting at
196.degree.-198.degree.C.
______________________________________ Analysis: C.sub.10 H.sub.10
ClN.sub.3 OS; molecular weight = 255.74 Calculated: C - 46.97%; H -
3.95%; N - 16.44%; Found: C - 47.10%; H - 4.03%; N - 16.30%;
______________________________________
Using the same procedure, the appropriate
2,4-dichloro-thieno[3,2-d]pyrimidine was reacted with the
appropriate amino compound to obtain the products in Table I.
TABLE I
__________________________________________________________________________
Product Melting point Crystallization in .degree.C from
__________________________________________________________________________
2-chloro-6-methyl-4-morpholino thieno[3,2-d]pyrimidine 180-181
acetone 2-chloro-4-(2-methyl-morpholino) thieno[3,2-d]pyrimidine
169-171 ethanol 2-chloro-4-(4-hydroxypiper-
idino)-thieno[3,2-d]pyrimidine 176-178 butanol
2-chloro-4-(4-methyl-pipera- zino)-thieno[3,2-d]pyrimidine 118-120
ethanol 2-chloro-4-pyrrolidino-thieno [3,2-d]pyrimidine 179-180
ethanol 2-chloro-4-hexamethyleneimino thieno[3,2-d]pyrimidine 89-90
ethanol 2-chloro-4-amino-thieno[3,2-d] pyrimidine 273-275 ethanol
2-chloro-4-(n-pentylamino)- absolute thieno[3,2-d]pyrimidine . HCl
206-208 ethanol 2-chloro-4-diethylamino-thieno petroleum
[3,2-d]pyrimidine 104-105 ether 2-chloro-4-piperidino-thieno
[3,2-d]pyrimidine 127-128 ethanol 2-chloro-4-dimethylamino-
thieno[3,2-d]pyrimidine 163 acetone 2-chloro-4-methylamino-thieno
acetone/ [3,2-d]pyrimidine 253 ethanol (1:1)
2-chloro-4-n-propylamino- petroleum eth- thieno[3,2-d]pyrimidine 96
er/ethyl ace- tate (10:1) 2-chloro-7-methyl-4-morpholino
thieno[3,2-d]pyrimidine 128 ethanol
__________________________________________________________________________
EXAMPLE IV
A solution of 19.4 gm (0.2 mol) of potassium thiocyanate in 20 cc
of water were added dropwise with stirring over 30 minutes to a
solution of 15.7 gm (0.1 mol) of methyl
3-amino-thiophene-2-carboxylate in 150 cc of hydrochloric acid
warmed to 70.degree.C and white crystals immediately began
precipitating. The reaction mixture was heated for 2 1/2 hours at
95.degree.C and the reaction mixture was vacuum filtered. The
crystalline precipitate was dissolved in 250 cc of 2N aqueous
sodium hydroxide with heating. The cooled solution was acidified
with glacial acetic acid whereby an analytically pure compound
precipitated out. After vacuum filtration, the crystals were washed
with water and dried to obtain 14.9 gm (81% yield) of
2-mercapto-4-oxy-thieno[3,2-d]pyrimidine melting above
300.degree.C.
______________________________________ Analysis: C.sub.6 H.sub.4
N.sub.2 OS.sub.2 ; molecular weight = 184.25 Calculated: C -
39.12%; H - 2.19% Found: C - 39.20%; H - 2.21%
______________________________________
EXAMPLE V
A solution of 10.0 gm (0.055 mol) of
2-mercapto-4-oxy-thieno[3,2-d]pyrimidine in 50 cc of aqueous sodium
hydroxide solution was slowly added with stirring at 50.degree.C to
30.0 gm of (0.275 mol) of ethyl bromide and then the reaction
mixture was refluxed for 2 hours. After cooling, the clear solution
was made acidic with glacial acetic acid and the mixture was vacuum
filtered. The crystalline precipitate was washed with water and
crystallized from ethanol to obtain 9.0 gm (77% yield) of 2-ethyl
mercapto-4-oxy-thieno[3,2-d]pyrimidine melting at
201.degree.-203.degree.C.
______________________________________ Analysis: C.sub.8 H.sub.8
N.sub.2 OS.sub.2 ; molecular weight = 212.30 Calculated: C -
45.26%; H - 3.80%; S - 30.21% Found: C - 45.40%; H - 3.85%; S -
30.13% ______________________________________
EXAMPLE VI
A mixture 0f 2.1 gm (0.011 mol) of 2-ethyl
mercapto-4-oxy-thieno[3,2-d]pyrimidine and 60.0 gm (1.0 mol) of
1,2-diamino ethane was heated for 10 hours at 160.degree.C in a
sealed tube. After cooling the reaction mixture, the excess amine
was distilled off in vacuo. The residue was subjected to
chromatography over a column of 0.2 - 0.5 mm silicagel with elution
with a 7:3 mixture of chloroform/methanol. The pure fractions were
evaporated to dryness and the residue was crystallized from a
petroleum ether/ethanol mixture to obtain 0.59 gm (28% yield) of
2-(2-aminoethylamino)-4-oxy-thieno[3,2-d]pyrimidine melting at
221.degree.C with decomposition.
EXAMPLE VII
A mixture of 2.1 gm (0.01 mol) of
2-(2-amino-ethylamino)-4-oxy-thieno[3,2-d]pyrimidine and 30 cc of
phosphorus oxychloride was refluxed for 2 hours and excess
phosphorus oxychloride was distilled off in vacuo from the
resulting clear solution. The residue was dissolved in water and
the aqueous solution was made alkaline with aqueous sodium
hydroxide solution with ice cooling. The aqueous phase was
extracted with methylene chloride and the organic extracts were
washed with water until the wash waters were neutral and then dried
over sodium sulfate and distilled to dryness. The solid residue was
crystallized from ethanol to obtain 0.48 gm (21% yield) of
2-(2-amino-ethylamino)-4-chloro-thieno[3,2-d]pyrimidine melting
above 300.degree.C.
______________________________________ Analysis: C.sub.8 H.sub.9
ClN.sub.4 S; molecular weight = 228.72 Calculated: C - 42.01%; H -
3.97%; Cl - 15.50% Found: C - 42.30%; H - 4.06%; Cl - 15.75%
______________________________________
EXAMPLE VIII
A mixture of 5.1 gm (0.02 mol) of
2-chloro-4-morpholino-thieno[3,2-d]pyrimidine and 15 cc of
5-amino-1-pentanol were heated at 120.degree.C for 4 hours and
after cooling, the clear solution was poured into water. An oil
separated which crystallized upon standing and then the reaction
mixture was vacuum filtered. The crystals were washed with water
and crystallized from 70% methanol to obtain 3.6 gm (57% yield) of
2-(5-hydroxypentylamino)-4-morpholine-thieno[3,2-d]pyrimidine
melting at 118.degree.-119.degree.C.
______________________________________ Analysis: C.sub.15 H.sub.22
N.sub.4 O.sub.2 S; molecular weight = 322.44 Calculated: C -
55.87%; H - 6.88%; N - 17.38% Found: C - 55.79%; H - 6.81%; N -
17.50% ______________________________________
Using the same method, the appropriate thieno [3,2-d]pyrimidine and
amino alcohol were reacted to obtain the compounds of Table II.
TABLE II
__________________________________________________________________________
Products Melting point Crystallized in .degree.C from
__________________________________________________________________________
2-(2-hydroxyethylamino)-4- morpholino-thieno[3,2-d] 122-123 acetone
pyrimidine 2-[(2-hydroxyethyl)-methylamino]
4-morpholino-thieno[3,2-d] 90-92 ether/methanol pyrimidine
2-(3-hydroxypropylamino)-4- ethanol/ethyl- morpholino-thieno[3,2-d]
238-239 acetate pyrimidine . HCl 2-(4-hydroxybutylamino)-4-
morpholino-thieno[3,2-d] 212 ethanol pyrimidine . HCl
2-(2-hydroxypropylamino)-4- morpholino-thieno[3,2-d] 243-244
ethanol pyrimidine . HCl 2-[(5-hydroxypentyl)-methyl-
amino]-4-morpholino-thieno 208-209 ethanol [3,2-d]pyrimidine . HCl
2-[(3-hydropropyl)-methylamino] ethanol/ 4-morpholino-thieno[3,2-d]
203 acetone pyrimidine . HCl (2:1) 2-[(3-hydroxypropyl)-ethylamino]
ethanol/ 4-morpholino-thieno[3,2-d] 235 acetone (2:1) pyrimidine .
HCl 2-[(4-hydroxybutyl)-methylamino] ethanol/
4-morpholino-thieno[3,2-d] 217 acetone (2:1) pyrimidine . HCl
2-[(4-hydroxybutyl)-ethylamino] ethanol/ 4-morpholino-thieno[3,2-d]
226-227 acetone (2:1) pyrimidine . HCl
2-[(4-hydroxybutyl)-n-propyl- ethanol/
amino]-4-morpholino-thieno[3, 160-163 acetone (2:1) 2-d]pyrimidine
. HCl 2-[(4-hydroxybutyl)-n-butyl- ethanol/
amino]-4-morpholino-thieno 162-165 acetone (2:1) [3,2-d]pyrimidine
. HCl 2-[(5-hydroxypentyl)-ethyl- amino]-4-morpholino-thieno
115-120 ethanol [3,2-d]pyrimidine . HCl 2-[(6-hydroxyhexyl)-methyl-
amino]-4-morpholino-thieno 115 ethanol [3,2-d]pyrimidine . HCl
2-[(6-hydroxyhexyl)-ethylamino] R.sub.f valve petroleum eth-
4-morpholino-thieno[3,2-d] Eluent: er/ethyl ace- pyrimidine = 0.5
tate (1:1) 2-[(5-hydroxypentyl)-butyl- isopropanol/
amino)-4-morpholino-thieno 90 petroleum [3,2-d]pyrimidine . HCl
ether
__________________________________________________________________________
EXAMPLE IX
18 gm (0.05 mol) of
2-(5-hydroxypentylamino)-4-morpholino-thieno[3,2-d]pyrimidine was
added to 30 cc of thionyl-chloride and the mixture was allowed to
stand overnight. Excess thionylchloride was distilled off in vacuo
and the residue was added to a mixture of acetone or ether. The
mixture was vacuum filtered and the crystalline precipitate was
dried to obtain 12.5 gm (66.3% yield) of
2-(5-chloropentylamino)-4-morpholino-thieno[3,2-d]pyrimidine . HCl
melting at 151.degree.-152.degree.C.
______________________________________ Analysis: C.sub.15 H.sub.22
Cl.sub.2 N.sub.4 O; molecular weight = 377.29 Calculated: C -
47.80%; H - 5.88%; N - 14.87% Found: C - 48.00%; H - 6.01%; N -
14.75% ______________________________________
Using the same procedure, thionyl chloride was reacted with the
appropriate thieno [3,2-d]pyrimidine to obtain the products of
Table III.
TABLE III
__________________________________________________________________________
Products Melting Crystallized from point in .degree.C
__________________________________________________________________________
2-[(5-chloropentyl)-meth- ylamino]-4-morpholino- 173-175
ethanol/acetone (1:1) thieno[3,2-d]pyrimidine . HCl
2-[(3-chloropropyl)-meth- ylamino]-4-morpholino- 180
ethanol/acetone (1:1) thieno[3,2-d]pyrimidine . HCl
2-[(4-chlorobutyl)-methyl- amino]-4-morpholino-thieno 205-208
ethanol/acetone (1:1) [3,2-d]pyrimidine . HCl
2-[(4-chlorobutyl)-ethyl- amino]-4-morpholino-thieno 165
ethanol/acetone (1:1) [3,2-d]pyrimidine . HCl
2-[(4-chlorobutyl)-n-pro- pylamino]-4-morpholino- 195
ethanol/acetone (1:1) . HCl 2-[(4-chlorobutyl)-n-
butylamino]-4-morpholino- 187-188 ethanol/acetone (1:1)
thieno[3,2-d]pyrimidine . HCl 2-[(5-chloropentyl)-eth-
ylamino]-4-morpholino- 183-185 ethanol/acetone (1:1)
thieno[3,2-d]pyrimidine . HCl 2-[(5-chloropentyl)-n- eluant :
petroleum butylamino]-4-morpholino- oil R.sub.f ether/ethyl acetate
thieno[3,2-d]pyrimidine value=0.8 (1:1) 2-[(6-chlorohexyl)-meth-
oil R.sub.f eluant : petroleum ylamino]-4-morpholino- value=0.8
ether/ethyl acetate thieno[3,2-d]pyrimidine (1:1)
2-[(6-chlorohexyl)-eth- oil R.sub.f eluant : petroleum
ylamino]-4-morpholino- value=0.8 ether/ethyl acetate
thieno[3,2-d]pyrimidine (1:1)
__________________________________________________________________________
EXAMPLE X
2.16 gm (0.01 mol) of
2-methylmercapto-4-chlorothieno[3,2-d]pyrimidine (produced from
phosphorus oxychloride and
2-methylmercapto-4-oxy-thieno[3,2-d]pyrimidine melting at
71.degree.-73.degree.C) were added to 30 cc of absolute ethanol and
then 1.74 gm (0.02 mol) of morpholine were added with stirring to
the reaction mixture while cooling to 20.degree.C. The reaction
mixture was then stirred for 3 hours at room temperature and was
then vacuum filtered. The precipitate was washed with water and
then ethanol and crystallized from ethanol to obtain 2.05 gm (77%
yield) of 2-methylmercapto-4-morpholino-thieno [3,2-d]pyrimidine
melting at 138.degree.-140.degree.C.
______________________________________ Analysis: C.sub.11 H.sub.13
N.sub.3 OS.sub.2 ; molecular weight = 267.38 Calculated: C -
49.44%; H - 4.90%; N - 15.72% Found: C - 49.21%; H - 4.95%; N -
15.84% ______________________________________
EXAMPLE XI
A solution of 3.5 gm (0.022 mol) of potassium permanganate in 25 cc
of water was added dropwise over 15 minutes to a solution of 2.67
gm (0.01 mol) of
2-methylmercapto-4-morpholino-thieno[3,2-d]pyrimidine in 25 cc of
glacial acetic acid and the reaction mixture was then stirred for 2
3/4 hours at 25.degree.C. The solution was decolored with a sodium
bisulfite solution and was then made alkaline by the addition of
aqueous sodium hydroxide solution. The aqueous phase was extracted
several times with methylene chloride and the combined methylene
chloride phases were washed with water, dried over sodium sulfate
and evaporated to dryness in vacuo. The residue was crystallized
from ethanol to obtain 1.84 gm (62% yield) of
2-methylsulfonyl-4-morpholino-thieno[3,2-d]pyrimidine melting at
191.degree.-193.degree.C.
______________________________________ Analysis: C.sub.11 H.sub.13
N.sub.3 O.sub.3 S.sub.2 ; molecular weight = 299.38 Calculated: C -
44.12%; H - 4.38%; N - 14.03% Found: C - 44.19%; H - 4.45%; N -
13.90% ______________________________________
EXAMPLE XII
A mixture of 2.1 gm (0.01 mol) of
2-(2-aminoethylamino)-4-oxy-thieno[3,2-d]pyrimidine and 2.5 gm
(0.011 mol) of phosphorus pentasulfide in 25 cc of absolute
pyridine was refluxed for 4 hours and the resulting clear solution
was evaporated to dryness in vacuo. The residue was added to 20 cc
of water and the mixture was refluxed for 1 hour and then was
colled to 5.degree.C. The pH of the solution was adjusted to 12 by
the addition of 2N aqueous sodium hydroxide and was then filtered
through charcoal. Glacial acetic acid was added to the solution
which caused the formation of a precipitate which was recovered by
vacuum filtration. The solid product was washed with water and
crystallized from dimethyl formamide to obtain 0.9 gm (40% yield)
of 2-(2-aminoethylamino)-4-mercapto-thieno[3,2-d]pyrmidine melting
at 249.degree.-250.degree.C (decomp.).
______________________________________ Analysis: C.sub.8 H.sub.10
N.sub.4 S.sub.2 ; molecular weight = 226.23 Calculated: C - 42.46%;
H - 4.45%; N - 24.76% Found: C - 42.33%; H - 4.47%; N - 24.57%
______________________________________
EXAMPLE XIII
2.26 gm (0.01 mol) of
2-(2-aminoethylamino)-4-mercapto-thieno[3,2-d]pyrimidine were
dissolved in 40 cc of 0.25N potassium hydroxide solution and after
cooling to 0.degree.C, 1.42 gm (0.01 mol) of methyl iodide were
added thereto with stirring. An oil soon separated and stirring was
continued for 2 hours at 0.degree.C. The mixture was extracted
several times with chloroform and the combined extracts were washed
with water, dried over sodium sulfate and evaporated to dryness.
The residue was crystallized from ether to obtain 1.9 gm (79%
yield) of 2-(2-aminoethylamino)-4-methylmercapto-thieno
[3,2-d]pyrimidine melting at 75.degree.C (decomp.).
______________________________________ ANALYSIS: C.sub.9 H.sub.12
N.sub.4 S.sub.2 ; molecular weight = 240.36 CALCULATED: %C 44.96 %H
5.03 %N 23.31 FOUND: 45.13 5.10 23.18
______________________________________
EXAMPLE XIV
A mixture of 5.2 gm (0.02 mols) of
2-chloro-4-morpholino-thieno[3,2-d]pyrimidine and 20 cc of
3-n-butylamino-propionitrile was heated at 150.degree.C for 10
hours and then excess 3-n-butylamino-propionitrile was distilled
off in vacuo. The residue was poured into water and the mixture was
extracted several times with methylene chloride. The methylene
chloride extracts were dried over sodium sulfate and evaporated to
dryness. The residue was purified by chromatography over a silica
gel column with elution with a 2-1 mixtrue of petroleum ether and
ethylacetate. The elution agent was distilled off and the resulting
yellow oil was dissolved in methanolic hydrochloride and the
addition of acetone caused the precipitation of 5.0 gm (64.4%
yield) of 2-[(2- cyanoethyl-n- butylamino[-4-morpholino-thieno
[3,2-d]pyrimidine hydrochloride which melted at
182.degree.-185.degree.C after crystallization from
isopropanol.
__________________________________________________________________________
ANALYSIS: C.sub.17 H.sub.24 N.sub.5 ClOS; molecular weight = 381.96
CALCULATED: %C 53.45 %H 6.33 %N 18.33 %Cl 9.27 %S 8.38 FOUND: 53.50
6.59 18.45 9.02 8.33
__________________________________________________________________________
Using the same procedure,
2-chloro-4-morpholinothieno[3,2-d]pyrimidine was reacted with
3-ethylaminopropionitrile and 3-methylamino-propioni to form
2-[(2-cyanoethyl)ethylamino]-4-morpholino-thieno [3,2-d] pyrimidine
hydrochloride melting at 180.degree.C and 2-[(2-cyanoethyl)
methylamino] -4-morpholino-thieno [3,2-d]pyrimidine hydrochloride
melting at 100.degree.-101.degree.C, respectively.
EXAMPLE 1
A mixture of 5.12 gm (o.02 mol) of
2-chloro-4-morpholino-thieno[3,2-d]pyrimidine and 20 cc of
1,2-diaminoethane was heated for 30 minutes at 120.degree.C and
after cooling, the reaction mixture was poured into a water-ice
mixture. The aqueous solution was made strongly alkaline by the
addition of a 30% aqueous sodium hydroxide solution and was then
extracted several times with methylene chloride. The combined
organic extracts were washed with water, dried over sodium sulfate
and evaporated to dryness. The non-crystalline residue was purified
by chromatography over a silica gel column with elution with
acetone-methanol (7-3) mixture and the pure fractions were
evaporated to dryness. The non-crystalline residue was dissolved in
absolute ether and precipitation was effected by addition of
etheral hydrochloric acid. The precipitate was recovered by vacuum
filtration, was washed with ether and was crystallized from
absolute ethanol to obtain 4.5 gm (64% yield) of
2-(2-aminoethylamino)-4-morpholino-thieno[3,2-d]pyrimidine
dihydrochloride melting at 282.degree.-283.degree.C (decomp).
______________________________________ ANALYSIS: C.sub.12 H.sub.17
N.sub.5 OS . 2HCl molecular weight = 352.30 CALCULATED: %C 40.91 %H
5.44 %N 19.88 %Cl 20.13 FOUND: 40.90 5.49 19.79 20.05
______________________________________
Using the same process, the appropriate thieno [3,2-d]pyrimidine
and diamino alkane were reacted to form the products of Table
IV.
TABLE IV
__________________________________________________________________________
Melting Solvent of PRODUCT Point Crystalliza- in .degree.C tion
__________________________________________________________________________
2-(2-aminoethylamino)-6-methyl 309-311 methanol
4-morpholino-thieno[3,2-d] (decomp) pyramidine 2HCl
2-[(2-aminoethyl)methylamino] 275 ethanol
4-morpholino-thieno[3,2-d] (decomp) pyrimidine-2HCl
2-(2-aminopropylamino)-4-mor- 214-216 ethanol
polino-thieno[3,2-d]pyrimidine (decomp) 2HCl 2-(2-amino-1-methyl
propylamino) 185 isopropanol 4-morpholino-thieno[3,2-d] (decomp)
pyramidine-2HCl 2-(3-aminopropylamino)-4-morpho- 255-258 ethanol
lino-thieno[3,2-d]pyrimidine (decomp) 2HCl
2-(4-aminobutylamino)-4-morpho- 245-247 methanol-
lino-thieno[3,2-d]pyrimidine (decomp) methyl-ethyl 2HCl ketone(1-2)
2-(6-aminohexylamino)-4-morpho- 280-282 ethanol-
lino-thieno[3,2-d]pyrimidine (decomp) acetone 2HCl (1-1)
2-(10-aminodecylamino)-4-morpho- 184-186 isopropanol-
lino-thieno[3,2-d]pyrimidine (decomp) acetone 2HCl (1-2)
2-(3-aminopropylamino)-4-amino- 129-130 ethanol
thieno[3,2-d]pyramidine 2-(2-aminoethylamino)-4-pentyl- 273-275
ethanol amino-thieno[3,2-d]pyrimidine- (decomp) 2HCl
2-(4-aminobutylamino)-4-n-propyl- 216-217 ethanol
amino-thieno[3,2-d]pyrimidine-2 acetone HCl (1-3)
2-(2-aminoethylamino)-4-(2-methyl- 276-278 ethanol
morpholino)-thieno[3,2-d]pyrimi- (decomp) dine - 2HCl
2-(2-aminoethylamino)-4-(4- 183-186 methanol
methylpiperazino)-thieno[3,2-d] (decomp) pyrimidine - 3HCl
2-(2-aminoethylamino)-4-(4- 247-249 ethanol
hydroxypiperidino-thieno[3,2-d] (decomp) pyrimidine-2HCl
2-(4-aminobutylamino)-4-hexa 123-125 ethanol-
methyleneimino-thieno[3,2-d] (decomp) acetone pyrimidine-2HCl (1-2)
2-(2-aminoethylamino)-4-piperi- 275-277 ethanol-
dino-thieno[3,2-d]pyrimidine acetone 2HCl (1-5)
2-(4-aminobutylamino)-4-piperidino- 219 ethanol-
thieno[3,2-d]pyrimidine-2HCl acetone (1-5)
2-(6-aminohexylamino)-4-piperidino- 281-283 ethanol-ace
thieno[3,2-d]pyrimidine-2HCl tone(1-5)
2-(3-aminopropylamino)-4-dimethyl- 269-271 methanol
amino-thieno[3,2-d]pyrimidine-2HCl
2-(4-aminobutylamino)-4-dimethyl- 280 ethanol
amino-thieno[3,2-d]pyrimidine-2HCl
2-(6-aminohexylamino)-4-dimethyl- 265-266 ethanol-
amino-thieno[3,2-d]pyrimidine-2HCl acetone 2-(4-aminobutylamino)-6
methyl-4- 315-316 ethanol morpholino-thieno[3,2-d]pyrimidine 2HCl
2-(5-aminopentylamino)-6-methyl-4- 302-305 ethanol
morpholino-thieno[3,2-d]pyrimidine 2HCl
2-(2-aminoethylamino)-7-methyl- 290 methanol
4-morpholino-thieno(3,2-d] (decomp) pyrimidine-2HCl
2-(5-aminopentylamino)-7-methyl- 250 ethanol
4-morpholino-thieno[3,2-d]Pyrimi- dine-2HCl
2-(2-aminoethylamino)-4-methylamino 280 ethanol
thieno(3,2-d)pyrimidine-2HCl (decomp) acetone(1-3)
2-(4-aminobutylamino)-4-methylamino 300 ethanol
thieno[3,2-d]pyrimidine-2HCl (decomp) acetone
2-(6-aminohexylamino)-4-methylamino- 241 ethanol
thieno[3,2-d]pyrimidine-2HCl acetone
2-(2-aminoethylamino)-4--n-propyl- 246-247 ethanol
amino-thieno[3,2-d]pyrimidine-2HCl acetone (1-3)
2-(2-aminoethylamino)-4-diethylamino- 165-166 methanol-
thieno[3,2-d]pyrimidine-2HCl (decomp) acetone (1-1)
__________________________________________________________________________
EXAMPLE 2
A mixture of 2.3 gm (0.01 mol) of
2-(2-aminoethylamino)-4-chloro-thieno[3,2-d]pyrimidine and 15 cc of
pyrrolidine was refluxed for 1 hour and the excess amine was
distilled off in vacuo. The residue was taken up in a 1N aqueous
sodium hydroxide solution and the solution was extracted several
times with methylene chloride. The combined extracts were washed
with water, dried over sodium sulfate and evaporated to dryness.
The non-crystalline residue was dissolved in absolute ether and the
addition of etheral hydrochloric acid caused a precipitate to form
which was recovered by vacuum filtration. The solid was washed with
ether and then was crystallized from absolute methanol to obtain
1.2 gm (36% yield) of
2-(2-aminoethylamino)-4-pyrrolidino-thieno[3,2-d]pyrimidine
dihydrochloride melting at 292.degree.-294.degree.C.
______________________________________ ANALYSIS: C.sub.12 H.sub.17
N.sub.5 S . 2HCl;molecular weight = 336.30 CALCULATED: %C 42.85 %H
5.69 %N 20.83 FOUND: 42.97 5.76 20.85
______________________________________
EXAMPLE 3
STEP A: A mixture of 16 gm (0.0424 mol) of
2-(5-chloropentylamino)-4-morpholino-thieno[3,2-d]pyrimidine
hydrochloride and a solution of 17.5 gm (0.094 mol) of potassium
phthalimide in 100 cc of dimethylformamide were heated at
145.degree.C for 14 hours after cooling, the reaction mixture was
added to water. The mixture was extracted with chloroform and the
chloroform phase was dried over sodium sulfate and evaporated to
dryness. The residue was triturated with a mixture of ethyl
acetate-petroleum ether and vacuum filtered to obtain 10 (52.3%
yield) of
2-(5-phthalimidopentylamino)-4-morpholino-thieno[3,2-d]pyrimidine
melting at 122.degree.-124.degree.C after crystallization from a
1-1 mixture of ethyl acetate petroleum ether.
STEP B: A solution of 2.15 gm (0.033 mol) of hydroxylamine
hydrochloride in 30 cc of ethanol was added to 15 cc of 4N
methanolic sodium methylate solution and the mixture was filtered
to remove precipitated sodium chloride. A solution of 3.82 gm
(0.00845 mol) of the phthalimido derivative produced in Step A in
20 cc of ethanol was added to the filtrate and the reaction mixture
was stirred for 2 hours at room temperature. The mixture was vacuum
filtered to remove the gelatinous precipitate of the sodium salt of
N-hydroxyphthalimide and the filtrate was added to methanolic
hydrochloric acid and then was evaporated to dryness. The
crystalline residue was crystallized from acetone-methanol mixture
to obtain 1.94 gm (58.1% yield) of
2-(5-aminopentylamino)-4-morpholino-thieno[3,2-d]pyrimidine
dehydrochloride melting at 254.degree.-256.degree.C.
______________________________________ ANALYSIS: C.sub.15 H.sub.25
Cl.sub.2 N .sub.5 OS; molecular weight = 394.29 CALCULATED: %C
45.70 %H 6.40 %N 17.79 %S 8.12 FOUND: 45.50 6.56 17.60 8.24
______________________________________
Using the same process, the appropriate
4-morpholino-thieno[3,2-d]pyrimidine was reacted first with
potassium phthalimide and then with hydroxylamine to obtain the
products in Table V.
TABLE V
__________________________________________________________________________
Melting Solvent for PRODUCT Point Crystalliza- in .degree.C tion
__________________________________________________________________________
2-[(5-aminopentyl)methylamino] 255-257 ethanol-
4-morpholino-thieno[3,2-d] acetone pyrimidine]2HCl (1-2)
2-[(4-aminobutyl)methylamino] 260 ethanol
4-morpholino-thieno[3,2-d] acetone pyrimidine-2HCl
2-[(4-aminobutyl)ethylamino ] 259-261 ethanol-
4-morpholino-thieno[3,2-d] acetone pyrimidine-2HCl
2-[(4-aminobutyl)n-propylamino 185 ethanol-
4-morpholino-thieno[3,2-d] acetone pyrimidine-2HCl
2-[(4-aminobutyl)-n-butylamino] 280 ethanol-
4-morpholino-thieno[3,2-d] acetone pyrimidine-2HCl
2-[(5-aminopentyl)-ethylamino] 236-238 ethylacetate-
4-morpholino-thieno[3,2-d] methanol pyrimidine-2HCl (3-1)
2-[(6-aminohexyl)methylamino] 227-228 ethanol
4-morpholino-thieno[3,2-d] pyrimidine-2HCl
2-[(6-aminohexyl)ethylamino] yellow oil eluant:
4-morpholino-thieno[3,2-d] Rf Value= methanol- pyramidine]2HCl 0.5
ammonia (9-1)
__________________________________________________________________________
EXAMPLE 4
A mixture of 3.77 gm (0.01 mol) of
2-(5-chloropentylamino)-4-morpholino-thieno[3,2-d]pyrimidine
hydrochloride and 50 cc of liquid ammonia were heated at
100.degree.C in a sealed tube for 16 hours after cooling, excess
ammonia was distilled off and the residue was purified by
chromotography over silica gel with elution with a 6-1 mixture of
methanol-ammonia. The residue was taken up in a small amount of
methanol and methanolic hydrochloric acid was added thereto
followed by addition of acetone which resulted in the precipitation
of 2-(5-aminopentylamino)-4-morpholino-thieno [3,2-d]pyrimidine
dihydrochloride which after crystallization from a acetone-methanol
mixture melted at 254.degree.-256.degree.C.
Using the same process, ammonia and
2-[(5-chloropentyl)methylamino]-4-morpholino-thieno[3,2-d]
pyrimidine hydrochloride was reacted to form
2-[(5aminopentyl)methylamino]-4-morpholino-thieno[3,2-d]pyrimidine
dihydrochloride which after crystallization from a 1-2 mixture of
ethanol-acetone melted at 255.degree.-257.degree.C.
EXAMPLE 5
A mixture of 2.67 gm (0.01 mol) of
2-methylmercapto-4-morpholino-thieno[3,2-d]pyrimidine, 65 cc of
1,2-diamino ethane and 65 cc of glacial acetic acid was refluxed
for 24 hours and then the reaction mixture was poured into water
and made alkaline with 30% aqueous sodium hydroxide. The aqueous
phase was extracted with methylene chloride several times and the
combined extracts were washed with water and evaporated to dryness.
The residue, which was a mixture of
2-(2-aminoethylamino)-4-morpholino-thieno [3,2-d]pyrimidine and
2-(2-acetamidoethylamino)-4-morpholino-thieno[3,2-d]pyrimidine, was
added to 30 cc of concentrate hydrochloric acid and the mixture was
refluxed for 8 hours and then cooled. The solution was made
alkaline with 30% aqueous sodium hydroxide and was extracted with
methylene chloride. The organic extracts were dried over sodium
sulfate and evaporated to dryness. The residue was dissolved in
ether and etheral hydrochloric acid was added thereto. The
resulting precipitate was recovered by vacuum filtration and was
crystallized from ethanol to obtain 1.6 gm (45% yield) of
2-(2-amino-ethylamino) -4-morpholino-thieno[3,2-d]pyrimidine
dihydrochloride melting at 282.degree.-283.degree.C. (decomp)
EXAMPLE 6
A mixture of 2.99 gm (0.01 mol) of 2-methylsulfonyl
-4-morpholino-thieno[3,2-d]pyrimidine and 25 cc of
1,2-diamino-ethane was heated at 80.degree.C for 30 minutes and the
reaction solution was concentrated to one-half its volume in vacuo
and was poured into a water-ice mixture. The aqueous solution was
made strongly alkaline by the addition of 30 % aqueous sodium
hydroxide and was then extracted several times with methylene
chloride. The organic phase was washed with water, dried over
sodium sulfate and evaporated to dryness. The residue was purified
by chomatography and was then dissolved in absolute ether.
Precipitation was effected by the addition of etheral hydrochloric
acid and the product was crystallized from absolute ethanol to
obtain 2.9 gm (82% yield) of
2-(2-aminoethylamino)-4-morpholino-thiene[3,2-d]pyrimidine
dihydrochloride melting at 282.degree.-283.degree.C. (decomp)
EXAMPLE 7
A mixture of 2.4 gm (0.01 mol) of
2-(2-aminoethylamino)-4-methylmercapto-thieno[3,2-d]pyrimidine, 50
cc of morpholine and 50 cc of glacial acetic acid was refluxed for
10 hours and was then poured into water. The aqueous solution was
made alkaline with 30% aqueous sodium hydroxide solution and
extracted several times with methylene chloride. The combined
extracts were washed with water and evaporated to dryness. The
residue, a mixture of
2-(2-aminoethylamino)-morpholino-thieno[3,2-d]pyrimidine and
2-(2-acetamidoethylamino)-4-morpholino-thieno[3,2-d] pyrimidine,
was added to 30 cc of concentrated hydrochloric acid and the
mixture was refluxed for 8 hours and then cooled. The mixture was
made alkaline with 30% aqueous sodium hydroxide solution and was
then extracted with methylene chloride. The methylene chloride
extracts were dried over sodium sulfate and evaporated to dryness.
The residue was dissolved in ether and addition of etheral
hydrochloride acid caused a precipitate to form. The precipitate
was crystallized from ethanol to obtain 1.9 gm (54% yield) of
2-(2-aminoethylamino)-4-morpholino-thieno [3,2-d]pyrimidine
dihydrchloride melting at 282.degree.-283.degree.C. (decomp)
EXAMPLE 8
A mixture of 20 cc of morpholine and 3.14 gm (0.01 mol) of
2-(2-acetylaminoethylamino)-4-methylsulfonylthieno[3,2-d]pyrimidine
(made by oxidation of
2-(2-acetamide-ethylamino)-4-methylmercapto-thieno[3,2-d]pyrimidine
with potassium permanganate) melting 229.degree.-231.degree.C was
heated at 75.degree.C for 30 minutes and the solution was
evaporated to dryness in vacuo. The residue was added to 30 cc of
concentrated hydrochloric acid and the mixture was refluxed for 8
hours and then was cooled. The mixture was made alkaline with 30%
aqueous sodium hydroxide solution and was extracted with methylene
chloride. The methylene chloride was washed with water, dried over
sodium sulfate and evaporated to dryness. The residue was dissolved
in ether and the addition of etheral hydrochloride acid thereto
caused a precipitate to form. Crystallization from ethanol gave 2.3
gm (65% yield) of
2-(2-aminoethylamino)-4-morpholinothieno[3,2-d]pyrimidine
dihydrochloride melting at 282.degree.-283.degree.C (decomp)
EXAMPLE 9
A mixture of 2.26 gm (0.01 mol) of
2-(2-aminoethylamino)-4-mercapto-thieno[3,2-d]pyrimidine and 40 cc
of morpholine was refluxed for 50 hours and excess amine was then
distilled off in vacuo. The residue was purified by chromatography
over silica gel and the free base was treated with etheral
hydrochloric acid followed by crystallization from ethanol to form
0.4 gm (11% yield) of
2-(2-aminoethylamino)-4-morpholino-thieno[3,2-d]pyrimidine
dihydrochloride melting at 282.degree.-283.degree.C. (decomp)
EXAMPLE 10
A mixture of 2.56 gm (0.01 mol) of
2-chloro-4-morpholino-thieno[3,2-d]pyrimidine and 4.08 gm (0.04
mol) of 1-acetylamino-2-aminoethane was heated at 120.degree.C for
2 hours and then cooled. The solution was poured into an ice water
mixture and was extracted several times with water. The organic
phase was washed with water, dried over sodium sulfate and
evaporated to dryness. The residue was crystallized from
isopropanol to obtain 2.5 gm (78% yield) of
2-(2-acetyl-aminoethylamino)-4-morpholino-thieno [3,2-d]pyrimidine
melting at 174.degree.-176.degree.C.
A mixture of 1.6 gm (0.005 mol) of
2-(2-acetylaminoethylamino)-4-morpholino-thieno[3,2-d]pyrimidine
and 15 cc of concentrated hydrochloric acid was refluxed for 8
hours and then was cooled. The reaction mixture was poured onto ice
and made strongly alkaline with a 30% aqueous sodium hydroxide
solution. The mixture was then extracted with methylene chloride
and the combined extracts were dried over sodium sulfate and
evaporated to dryness. The non-crystalline residue was dissolved in
absolute ether and the addition of etheral hydrochloric acid caused
formation of a precipitate which was crystallized from absolute
ethanol to obtain 0.7 gm (40% yield) of
2-(2-aminoethylamino)-4-morpholino-thieno[3,2-d]pyrimidine
dihydrochloride melting at 282.degree.-283.degree.C (decomp).
EXAMPLE 11
10.7 gm (0.035 mol) of
2-[(2-cyanoethyl)methylamino]-4-morpholino-thieno[3,2-d]pyrimidine
were dissolved in 200 cc of methanolic ammonia and the mixture was
hydrogenated for 8 hours at room temperature with a hydrogen
pressure of 100 atmospheres in an autoclave with 10 gm of Raney
nickel. The catalyst was filtered off and the filtrate was
evaporated to dryness. The residue was added to water and the pH of
the resulting solution was adjusted to 6 by the addition of dilute
hydrochloric acid. The reaction mixture was extracted with
chloroform, the aqueous phase was made alkaline and was extracted
again with chloroform. The chloroform phase was dried over sodium
sulfate and evaporated to dryness. The residue was dissolved in
isopropanol and the addition resulted in the precipitation of 5.2
gm (39.1% yield) of 2-[(3-aminopropyl)
methylamino]-4-morpholino-thieno[3,2-]pyrimidine dihydrochloride
which after crystallization from ethanol melted at
245.degree.-248.degree.C.
By the same process, 2-[(2-cyanoethyl)ethylamino]
-4-morpholino-thieno[3,2-d]pyrimidine and 2-[(2-cyanoethyl)
n-butylamino]-4-morpholino-thieno[3,2-d]pyrimidine were
hydrogenated using a Raney nickel catalyst to obtain
2-[(3-aminopropyl)ethylamino]-4-morpholino-thieno[3,2-d] pyrimidine
dihydrochloride melting at 280.degree.C and
2-[(3-aminopropyl)n-butylamino]-4-morpholino-thieno[3,2-d]
pyrimidine dihydrochloride melting at 279.degree.-281.degree.C
after crystallization from isopropanol.
EXAMPLE 12
A mixture of 2.56 gm (0.01 mol) of
2-chloro-4-morpholino-thieno[3,2-d]pyrimidine and 7.68 gm (0.03
mol) of 2-(p-toluene sulfonamido)-ethyl ethylamine was heated for 6
hours at 140.degree.C and after cooling, the light yellow solution
was poured into water. The mixture was extracted with methylene
chloride and extracts were dried over sodium sulfate and evaporated
to dryness. The residue was purified by chromatography over silica
gel with elution with a mixture of benzene-acetone-methanol
(60-25-15) and evaporation of the mixed solvent to obtain 4.0 gm
(87% yield) of 2-[2-(p-toluene sulfonamido)ethyl
ethylamino]-4-morpholino-thieno[3,2-d]pyrimidine melting at
123.degree.-125.degree.C after crystallization from methanol. The
free base was reacted with methanolic hydrochloric acid to obtain
the corresponding hydrochloride salt melting at
249.degree.-251.degree.C after crystallization (from-methanol).
__________________________________________________________________________
ANALYSIS: C.sub.21 H.sub.28 ClN.sub.5 O.sub.3 S.sub.2 ; molecular
weight = 498.08 CALCULATED: %C 50.64 %H 5.67 %N 14.06 %Cl 7.12 %S
12.87 FOUND: 50.85 5.74 13.95 7.19 12.60
__________________________________________________________________________
A mixture of 4.6 gm (0.01 mol) of 2-[2-(p-toluene sulfon
amido)ethyl ethylamino]-4-morpholino-thieno [3,2-d]pyramidine and
50 cc of a 40% solution of hydrobromic acid in glacial acetic acid
and 1.8 gm (0.02 mol) of phenol were heated at 60.degree.C for 6
hours and then the solvent was distilled off under reduced
pressure. The residue was added to water and the solution was made
strongly acidic with hydrochloric acid. The aqueous phase was
extracted with ethyl ether and then was made alkaline while cooling
by the addition of potassium carbonate. The solution was extracted
with methylene chloride and the methylene chloride was dried over
sodium sulfate and evaporated to dryness. The oily residue was
added to methalonic hydrochloric acid to obtain 1.2 gm (32% yield)
of 2-[(2-aminoethyl)-ethylamino]-4-morpholino-thieno[3,2-d]
pyrimidine dihydrochloride melting at 284.degree.-285.degree.C
after crystallization from ethanol.
______________________________________ ANALYSIS: C.sub.14 H.sub.23
Cl.sub.2 N.sub.5 OS; moleculat weight = 380.27 CALCULATED: %N 18.45
%Cl 18.65 %S 8.42 FOUND: 18.25 18.40 8.23
______________________________________
Using the same process, hydrobromic acid in glacial acetic acid was
reacted with the appropriate thieno [3,2-d]pyrimidine to obtain the
products of Table VI:
TABLE VI
__________________________________________________________________________
Melting Solvent of PRODUCTS Point Crystalliza- in .degree.C tion
__________________________________________________________________________
2-[(2-aminoethyl)methylamino]-6- 293-295 ethanol
methyl-4-morpholino-thieno[3,2-d] pyrimidine-2HCl
2-[(2-aminoethyl)n-propylamino] 273-275 methanol
4-morpholino-thieno[3,2-d] pyramidine-2HCl
2-[(2-aminoethyl)isopropylamino] 278-280 ethanol
4-morpholino-thieno[3,2-d] pyrimidine-2HCl
2-[(2-aminoethyl)-n-butylamino] 271-274 ethanol
4-morpholino-thieno[3,2-d] pyramidine-2HCl
2-[(3-aminopropyl)ethylamino] 280 ethanol
4-morpholino-thieno[3,2-d] pyrimidine-2HCl
2-[(3-aminopropyl)-n-propylamino] 291-293 ethanol
4-morpholino-thieno[3,2-d] pyrimidine-2HCl
__________________________________________________________________________
2-[(3-benzamidopropyl)methylamino]-4-morpholinothieno[3,2-d]pyrimidine
was hydrolized by refluxing with concentrated hydrochlorid acid to
obtain a 34% yield of
2-[(3-aminopropyl)methylamino]-4-morpholino-thieno[3,2-d]
pyrimidine dihydrochloride melting at 245.degree.-248.degree.C
after crystallization from a 1-5 mixture of ethanol-acetone.
______________________________________ ANALYSIS: C.sub.14 H.sub.23
Cl.sub.2 N.sub.5 OS; molecular weight - 380.35 CALCULATED: %C 44.20
%H 6.09 %S 8.43 FOUND: 43.95 6.18 8.14
______________________________________
EXAMPLE 13
A mixture of 2.87 gm (0.01 mol) of
2-chloro-4-diethanolamino-7-methyl-thieno[3,2-d]pyrimidine
(prepared from diethanolamine and 2,4-dichloro-7-methyl-thieno
[3,2-d] pyrimidine) and 10 cc of 1,2-diaminoethane were heated at
120.degree.C for 4 hours and the excess amine was distilled off in
in vacuo. The residue was purified by chromatography over silica
gel with elution with a 9-1 mixture of methanol-concentrated
ammonium hydroxide. The pure fractions were evaporated to dryness
and the non-crystalline residue was dissolved in excess ethanolic
hydrochloric acid and the solution was evaporated by dryness. The
residue was crystallized from a 3-1 mixture of methanol-ethanol to
obtain 2.6 gm (68% yield) of
2-[(2-aminoethylamino)-4-diethanolamino- 7-methyl-thieno
[3,2-d]pyrimidine dihydrochloride melting at 235.degree.C
(decomp).
______________________________________ ANALYSIS: C.sub.13 H.sub.23
Cl.sub.2 N.sub.5 O.sub.2 S; molecular weight = 384.34 CALCULATED:
%C 40.62 %H 6.03 %N 18.22 FOUND: 40.45 6.18 18.11
______________________________________
3.84 gm of (0.01 mol) of
2-(2-aminoethylamino)-4-diethanolamino-7-methyl-thieno[3,2-d]pyrimidine
dihydrochloride were dissolved in 50 cc of concentrated sulfuric
acid and the mixture was allowed to stand for 3 days at 20.degree.C
in the absence of moisture. The reaction mixture was poured into a
water-ice mixture and was then made alkaline with a 40% aqueous
sodium hydroxide solution. The mixture was extracted several times
with methylene chloride and the combined extracts were washed with
water, dried over sodium sulfate and then added to etheral
hydrochloric acid. The resulting precipitate of
2-(2-aminoethylamino)-7-methyl-4-morpholino-thieno[3,2-d]pyrimidine
dihydrochloride was recovered by filtration, was washed with ether
and crystallized from methanol to obtain 1.98 gm (54% yield) of the
said dihydrochloride melting at 335.degree.C (decomp).
______________________________________ ANALYSIS: C.sub.13 H.sub.21
Cl.sub.2 N.sub.5 OS; molecular weight = 366.33 CALCULATED: %C 42.70
%H 5.77 %N 19.10 FOUND: 42.50 5.88 18.95
______________________________________
Using the same procedure, the appropriate
4-diethanolamino-thieno[3,2-d]pyrimidine dihydrochloride was
treated with concentrated sulfuric acid to obtain the products of
Table VII.
TABLE VII
__________________________________________________________________________
Melting Solvent of PRODUCTS Point Crystalliza- in .degree.C tion
__________________________________________________________________________
2-[(3-aminopropyl)ethylamino] 280 ethanol
4-morpholino-thieno[3,2-d] pyrimidine.2HCl
2-[(5-aminopentyl)ethylamino] 236-238 ethyl
4-morpholino-thieno[3,2-d] acetate pyrimidine.2HCl methanol(3-1)
2[(6-aminohexyl)methylamino] 227-228 ethanol
4-morpholino-thieno[3,2-d] pyrimidine.2HCl
2[(4-aminobutyl)n-butylamino] 280 ethanol-
4-morpholino-thieno[3,2-d] acetone pyrimidine. 2HCl
2-[(2-aminoethyl)isopropylamino] 278-280 ethanol
4-morpholino-thieno[3,2-d] pyrimidine.2HCl
2-[(2-aminoethylamino)-4-morpholino 282-283
thieno[3,2-d]pyrimidine.2HCl (decomp)
2-(2-aminoethylamino)-6-methyl 309-311 methanol
4-morpholino-thieno[3,2-d] (decomp) pyrimidine.2HCl
2-[(2-aminoethyl)methylamino] 275 ethanol
4-morpholino-thieno[3,2-d] (decomp) pyrimidine.2HCl
2-(2-aminopropylamino)-4- 214-216 ethanol morpholino-thieno[3,2-d]
(decomp) pyrimidine.2HCl 2-(3-aminopropylamino)-4- 255-258 ethanol
morpholino-thieno[3,2-d] (decomp) pyrimidine.2HCl
2-(4-aminobutylamino)-4-mor- 245-247 methanol-
pholino-thieno[3,2-d]pyrimi- (decomp) methyl ethyl dine.2HCl ketone
(1-2) 2-(6-aminohexylamino)-4- 280-282 ethanol-
morpholino-thieno[3,2-d] (decomp) acetone pyrimidine.2HCl (1-1)
2-[(5-aminopentyl)methylamino] 255-257 ethanol-
4-morpholino-thieno[3,2-d] actone pyrimidine.2HCl (1-2)
__________________________________________________________________________
EXAMPLE 14
Using the procedure of Example 13,
2-(2-aminoethylamino)-4-[N-(2-hydroxyethyl)-2hydroxypropylamino]-thieno
[3,2-d]pyrimidine dihydrochloride was treated with concentrated
sulfuric acid to obtain 2-(2-aminoethylamino)
-4-(2-methylmorpholino)thieno[3,2-d]pyrimidine dihydrochloride
melting at 276.degree.-278.degree.C(decomp) after crystallization
from ethanol
EXAMPLE 15
2-[5-(p-toluene sulfonamide-pentyl)-methylamino]
-4-diethanolamino-thieno[3,2-d]pyrimidine was treated with
concentrated sulfuric acid and the resulting product was hydrolyzed
with hydrobromic acid in glacial acetic acid in the presence of a
small amount of phenol at 60.degree.C to obtain
2-[(5-aminopentyl)methylamino]-4-morpholino-thieno
[3,2-d]pyrimidine dihydrochloride melting at
255.degree.-257.degree.C.
PHARMOLOGICAL EXAMPLES
EXAMPLE A
Tablets with 30 mg of
2-(2-aminoethylamino)-4-morpholino-thieno[3,2-]pyrimidine
dihydrochloride
COMPOSITION: 1 tablet contains
2-(2-aminoethylamino)-4-morpholino-thieno [3,2-d]pyrimidine
dihydrochloride 30.0 mg lactose 38.0 mg potato starch 26.0 mg
polyvinylpyrrolidone 5.0 mg magnesium stearate 1.0 mg 100.0 mg
COMPOUNDING PROCEEDURE
The active ingredient was mixed with lactose and potato starch,
moistened equally with a 20% ethanolic solution of the
polyvinylpyrrolidone and granulated through a 1.5 mm mesh screen.
The granulate was dried at 45.degree.C and again passed through a
1.0 mm mesh screen and the thus obtained granulate was then mixed
with magnesium stearate and pressed into flat 7 mm tablets weighing
100 mg each.
EXAMPLE B
Coated tablets with 15 mg of
2-(4-aminobutylamino)-4-morpholino-thieno[3,2-d]pyrimidine
dihydrochloride
COMPOSITION: 1 core of coated tablet contains
2-(4-aminobutylamino)-4-morpholino-thieno- [3,2-d]pyrimido
dihydrochloride 15.0 mg lactose 14.0 mg corn starch 8.0 mg
polyvinylpyrrolidone 2.5 mg magnesium stearate 0.5 mg 40.0 mg
COMPOUNDING PROCEDURE
The active ingredient was mixed with lactose and corn starch,
moistened equally with a 20% ethanolic solution of the
polyvinylpyrrolidone and granulated through a screen of 1.5 mm mesh
size. The granulate was dried at 45.degree.C and again passed
through a 1.0 mm mesh screen. The thus obtained granulate was mixed
with magnesium stearate and pressed into convex 5.0 mm cores of
coated tablets weighing 40 mg. The thus obtained cores were coated
according to known methods with a shell consisting essentially of
sugar and talcum. The finished coated tablets were polished by
means of beeswax and weighed 70.0 mg each.
EXAMPLE C
Ampoules with 10 mg of
2-(2-aminoethylamino)-4-morpholino-thieno[3,2-d]pyrimidine-dihydrochloride
COMPOSITION: 1 ampoule contains
2-(2-aminoethylamino)-4-morpholino-thieno- [3,2-d]pyrimidine
dihydrochloride 10.0 mg polyethylene glycol 600 100.0 mg distilled
water ad 2.0 cc
COMPOUNDING PROCEEDURE
The polyethylene glycol and the active ingredient were dissolved in
boiled, distilled water cooled while introducing nitrogen. The
solution was filled up to the indicated volume with distilled water
and filtered sterile. All work must be effected in diffuse light.
The liquid was poured into brown 2 cc ampoules while nitrogen
gasing and sterilized for 20 minutes at 120.degree.C.
EXAMPLE D
Drops with 10 mg of
2-(4-aminobutylamino)-4-morpholino-thieno-[3,2-d]pyrimidine
dihydrochloride
COMPOSITION: 1 ml of drop solution contains
2-(4-aminobutylamino)-4-morpholino-thieno- [3,2-d]pyrimidine
dihydrochloride 10.0 mg cane sugar 350.0 mg sorbic acid 1.0 mg
cocoa essence 50.0 mg ethyl alcohol 0.2 cc polyethylene glycol 600
0.1 cc distilled water ad 1.0 cc
COMPOUNDING PROCEEDURE
The sorbic acid was dissolved in alcohol and mixed with the same
quantity of water. Then the active ingredient was dissolved in the
solution (solution 1). The sugar was dissolved in the remaining
water (solution 2).
Solution 2, polyethylene glycol 600 and the cocoa essence were
added to solution 1 while stirring and the resulting solution was
filtered through a suitable filter. 1 ml of drop solution contained
10 mg of 2-(4-aminobutylamino)-4-morpholino-thieno[3,2-d]pyrimidine
dihydrochloride. The production, filling and storage of the
solution must be done under a nitrogen atmosphere.
PHARMACOLOGICAL STUDY
INHIBITION OF PLATELET AGGREGATION
The inhibition of platelet aggregation was determined by three
different methods. The first method was that of K. Breddin
[Schweiz. Med. Wschr. Vol 95, 655-660 (1965)] wherein human blood
plasma rich in platelets was, after the addition of the test
compound, slowly rotated in a water bath. A siliconized glass
holder was subsequently covered with the rotated plasma, washed,
fixed and colored. The inhibition of the aggregation of the
platelets was determined microscopically.
The second method for the determination of the inhibition of
platelet-aggregation was that of Born et al. [J. Physiol. Vol. 170,
397 (1964)]. The aggregation was measured in the plasma rich in
platelets of healthy test persons. The decrease of the optical
density in the suspension of platelets was measured and registered
photometrically after addition of adenosin-diphosphate
(10.sup..sup.-5 mols per liter). The active substances were each
added 10 minutes before the addition of adenosin-diphosphate.
The third test for aggregation of platelets was that of Morris [1.
Internationales Symposium ueber Stoffwechsel und
Membranpermeabilitat von Erythrozyten und Thrombozyten, Wien 1968,
E. Deutsch, E. Gerlach, K. Moser; Georg Thieme-Verlag Stuttgart].
Human citrated blood was brought into contact for 30 seconds with 1
gm of glass-balls. After the contact the blood was allowed to stand
for 1 hour to render possible the desaggregation of the reversible
aggregates. The platelets in the plasma were counted
microscopically before and after the contact with glass-balls.
According to these 3 test methods, the following substances showed
a good inhibition of the aggregation of platelets still at a
concentration of 10.sup..sup.-5 mols per liter:
2-[(5-aminopentyl)ethylaamino]-4-morpholino-thieno [3,2-d]
pyrimidine dihydrochloride.
2-[(5-aminopentyl)methylamino]-4-morpholino-thieno [3,2-d]
pyrimidine dihydrochloride.
2-[(3-aminopropyl)ethylamino]-4-morpholino-thieno [3,2-d]
pyrimidine dihydrochloride.
2-[(2-aminoethyl)ethylamino]-4-morpholino-thieno [3,2-d] pyrimidine
dihydrochloride.
2-(2-aminoethylamino)-4-morpholino-thieno [3,2-d] pyrimidine
dihydrochloride.
2-(3-aminopropylamino)-4-morpholino-thieno [3,2-d] pyrimidine
dihydrochloride.
2-(4-aminobutylamino)-4-morpholino-thieno [3,2-d] pyrimidine
dihydrochloride.
2-[(2-animoethyl)methylamino]-4-morpholino-thieno [3,2-d]
pyrimidine dihydrochloride and
2-(2-aminopropylamino)-4-morpholino-thieno [3,2-d] pyrimidine
dihydrochloride.
Various modifications of the compositions and methods of the
invention may be made without departing from the spirit or scope
thereof and it is to be understood that the invention is to be
limited only as defined in the appended claims.
* * * * *